PROJECT SUMMARY (Joshua Buss) A critical element of pharmaceutical development is the identification of a core structure of interest and the exploration of the chemical space surrounding said structure; often subtle structural changes can have profound effects on the efficacy of a drug candidate. As small molecule medicines are being developed to combat topical ailments at the forefront of human health, they are increasing in complexity and becoming progressively difficult, time consuming, and expensive to synthesize. Late-stage diversification of a drug molecule facilitates the rapid screening of related structures without the need to develop multi-step de novo syntheses. Such reactions need to be selective for a functional handle present in the molecule of interest, proceed in reasonable yield, and demonstrate compatibility with the various functional groups present in leading pharmacophores. This proposal outlines the development of two new Ni-catalyzed enantioselective benzylic C?H bond functionalization reactions. Benzylic C?H bonds are prevalent in pharmaceuticals due to the commonality of arenes moieties and are often associated with undesirable pharmacokinetics due to oxidative degradation by cytochrome P450. A common solution to this problem is to block these metabolic ?hot spots? with fluorine or methyl groups. Benzylic fluorination is a burgeoning field of reaction development, but asymmetric C?H fluorination is still rare and is limited to a handful of specialized substrates. C(sp2)?H methylation chemistry has seen recent advances, but C(sp3)?H methylation is lagging behind. Herein, we propose the use of Kharasch-Sosnovsky-type chemistry to generate benzylic radicals that are subsequently trapped at chiral Ni complexes. N-fluorosulfonyl imide (NFSI) will be employed as both the oxidant and source of fluorine in the fluorination reactions. The mechanism of this reaction will be studied in detail using a combination of spectroscopic techniques, electrochemistry, independent synthesis, reaction kinetics, radical traps, and isotopic labeling, with a particular focus on understanding the fundamental steps of precatalyst activation, benzylic radical formation, and C?F bond formation. A single-component methylation reaction using bulky dialkyl peroxides as both the oxidant and the source of methyl (methyl radical formation following alkoxy radical ?-scission) is proposed and discussed. Understanding the potential difficulty of engendering cross- selectivity in the coupling of two transient radicals, a two-component oxidant/nucleophile methodology for enantioselective benzylic methylation is also outlined. The development of the proposed methods, and the detailed understanding of how they proceed, will provide applicable tools for drug discovery, facilitating the innovation of more potent, less toxic medicines.